Schizophrenic individuals show abnormalities in event related potentials (ERPs) and in the gamma and theta frequency components of these ERPs. Marked abnormalities occur in gamma and theta oscillations elicited by novel or deviant (unpredicted) stimuli. The goal of this project is to investigate, using detailed computer simulations, how these gamma, theta, and ERP abnormalities may arise from cellular and synaptic pathology in cortex. Recent studies have uncovered basic mechanisms by which gamma and theta oscillations are generated in cortex?both gamma and theta arise from the same cortical microcircuit involving pyramidal cells and two types of interneurons. Each cell type plays a different role in generating gamma vs. theta. Based on data from the literature, and findings from Subprojects 0007, 0008, and 0009, we will develop a detailed biophysical level simulation of this microcircuit, and we will examine the circuit mechanisms that underlie robust generation of theta and gamma, particularly the role of dendritic gap junctions. We hypothesize that synaptic facilitation and depression, in celltype specific connections, alters the balance between gamma and theta;thus, abnormalities in short-term plasticity may underlie the excess gamma and decreased theta seen in schizophrenic patients. We propose a specific circuit model for how the cortex responds to novel versus familiar stimuli?the circuit involves known connections between cortical layers III and V. Glutamtatergic dysfunction, as reported in schizophrenia, will lead to predicted failures in this novelty detection mechanism, and to associated abnormalities in gamma oscillations and the mismatch negativity in the ERP. We focus on understanding the NMDA antagonist actions of ketamine, which produces gamma/theta abnormalities similar to those in schizophrenia, and which is known to induce disassociative symptoms. We hypothesize that phenytoin, which blocks persistent sodium channels, will reverse the gamma and theta abnormalities induced by ketamine, and also possibly in animal and human models. Perception, cognition, and memory are associated with specific electrical signatures in the brain? oscillations of cell firing at low (theta) and high (gamma) frequencies. We will investigate how these oscillations are generated by specific circuits in the cerebral cortex, and how abnormalities in synaptic signaling reported in schizophrenic brains give rise to these altered oscillations. This understanding may lead to insight into how schizophrenia affects cognitive processes, and to the cellular mechanisms responsible for the symptoms of the disease.